2.1 Ovarian Cancer
Ovarian cancer is the third most common malignant tumor and the fifth leading cause of cancer death in women. Only 39% of all women with ovarian cancer survive for 5 years. Ovarian cancer is a deadly disease that accounted for about 13,600 deaths in the United States in 1994 as well as some 24,000 new cases (Boring et al., 1994, CA Cancer J. Clin. 44:7–26). Ovarian cancer is more common in industrialized nations, with the exception of Japan. The average age of diagnosis of women with ovarian cancer is almost 60. The incidence of ovarian cancer is 16 per 100,000 women who are 40 years of age and old. This number increases to 56 per 100,000 women who are 70 years of age and older. More than half of the deaths from ovarian cancer occur in women between 55 and 74 years of age. Approximately one quarter of ovarian cancer deaths occur in women between 35 and 54 years of age.
There are several well recognized risk factors for ovarian cancer. Older women have a higher risk of developing ovarian cancer. The more children a woman has, the lower her risk of ovarian cancer. Early age at first pregnancy and the use of oral contraceptive pills have also been shown to have a protective effect. In contrast, the use of fertility drugs has been associated with an increased chance of developing ovarian cancer. Family history is the single most important risk factor for the development of ovarian cancer. Those with breast cancer also are at higher risk. Ovarian cancer in two or more first-degree relatives (mother or sister) suggests a hereditary cause. A family history of colon, lung, prostate, and uterine cancers may indicate the presence of a Lynch II syndrome, which may also confer a higher risk for developing ovarian cancer. White women are about 70 percent more likely than black women to get ovarian cancer (Parazzini et al., 1991, Gynecol Oncol. 41:1–16). Other factors include talc use, asbestos exposure, early menstruation or menopause, high dietary fat content, and childhood mumps infection are controversial and have not been definitively proven.
The symptoms of ovarian cancer are vague and nonspecific. Common symptoms include abdominal pain, abdominal swelling, bloating or dyspepsia, pelvic pressure, weight gain or loss, abnormal menstrual cycles, increased abdominal girth, vaginal bleeding, excessive hair, and increased urinary frequency or urgency. In 60% to 70% of the patients, by the time the cancer is diagnosed, the tumor has often spread beyond the ovaries. Ovarian cancers shed malignant cells which frequently implant on the uterus, bladder, bowel, and omentum and often begin forming new tumor growths before cancer is even suspected. Currently used screening tests include CBC, blood chemistry, CA125, quantitative serum HCG (blood pregnancy test), alpha fetoprotein (AFP), urinalysis, GI series, laparotomy exploratory, ultrasound, abdominal CT scan or MRI. Unfortunately, the only sure way to know is by biopsy. Over 50 percent of women with ovarian cancer are diagnosed in the advanced stages of the disease.
Ovarian neoplasms are classified according to cell of origin. There are three major types of ovarian cancer, those arising from the celomic epithelium (60% to 70% of cases), specialized stroma (5% to 10%), and germ cell layer (or unfertilized ovum) (15% to 20%). The most common ovarian tumor is serous carcinoma, which tends to grow rapidly with early intraperitoneal spread.
The staging of ovarian cancer is based on the revised criteria of TNM staging by the American Joint Committee for Cancer (AJCC) published in 1988. Staging is the process of describing the extent to which cancer has spread from the site of its origin. It is used to assess a patient's prognosis and to determine the choice of therapy. The stage of a cancer is determined by the size and location in the body of the primary tumor, and whether it has spread to other areas of the body. Staging involves using the letters T, N and M to assess tumors by the size of the primary tumor (T); the degree to which regional lymph nodes (N) are involved; and the absence or presence of distant metastases (M)—cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. Each of these categories is further classified with a number 1 through 4 to give the total stage. Once the T, N and M are determined, a “stage” of I, II, III or IV is assigned. Stage I cancers are small, localized and usually curable. Stage II and III cancers typically are locally advanced and/or have spread to local lymph nodes. Stage IV cancers usually are metastatic (have spread to distant parts of the body) and generally are considered inoperable.
Treatment options for ovarian cancer include surgery, radiation therapy, hormone therapy, chemotherapy, and vaccines comprising monoclonal antibodies that blocks growth-factor receptors on the surface of cancer cells and thereby, preventing the activation and growth of cancer cells. Surgery is the most common treatment for ovarian cancer and involves removing the ovary as well as some tissue surrounding it. During the surgery, a sample of the lymph nodes in nearby tissue is usually removed to better assess whether the cancer has spread beyond the ovary. Survival has been shown to correlate strongly with residual disease. Aure and coworkers reported improvements in the 5-year survival of Stage II patients (from 18% to 55%) and Stage III patients (from 8% to 30%) who were optimally resected. (1971, Obstet Gynecol. 37:1) However, one permanent side effect of surgery is infertility.
Radiation therapy is the second most common treatment. For the treatment of ovarian cancer, the high-energy rays can be delivered by two basic methods: external beam (similar to an x-ray) or brachytherapy (internal radiation delivered with implanted radioactive seeds). Fatigue is a possible side effect of radiation therapy, but it gradually ceases after treatment is completed. Some women may also experience bowel problems, urinary problems, and rectal discomfort or bleeding. Depending on how extensive the cancer is or how big the tumor has grown, hormone therapy may be used before radiation therapy to help shrink the size of the tumor, thereby making it easier to treat. Hormone therapy decreases the amount of the male hormone testosterone in the body, which can promote the growth of cancer cells.
Chemotherapy is used primarily in cases where the disease has spread outside the ovary and where hormonal treatments alone are no longer effective in preventing tumor growth. Potential side effects include nausea and vomiting, loss of hair, low blood cell counts, and fatigue. Many chemotherapeutic drugs have been tried in the past as single agents for the palliation of ovarian cancer, but the results were generally disappointing. Nevertheless, the role of chemotherapy in the management of ovarian cancer is continually evolving. Oftentimes, chemotherapy with radiation in adjunct to surgery is used. In general, chemotherapy can achieve long-term survival rates of up to 15% to 20%, even in patients with recurrent or metastatic disease (Ali et al., 2000, Oncology 14(8):1223–30). Unfortunately, the high initial response rates to first line chemotherapy does not appear to translate into a survival benefit (Kohno and Kitahara, 2001, Gan To Kagaku Ryoho 28(4):448–53). Moreover, there are many undesirable side effects associated with chemotherapy such as temporary hair loss, mouth sores, anemia (decreased numbers of red blood cells that may cause fatigue, dizziness, and shortness of breath), leukopenia (decreased numbers of white blood cells that may lower resistance to infection), thrombocytopenia (decreased numbers of platelets that may lead to easy bleeding or bruising), and gastrointestinal symptoms like nausea, vomiting, and diarrhea. Active chemotherapeutic agents include mitoxantrone, prednisone, paclitaxel, docetaxel, estramustine, adriamycin, estramustine phosphate (Emcyt®), and mitoxantrone (Novantrone®).
The identification of active chemotherapeutic agents against cancers traditionally involved the use of various animal models of cancer. The mouse has been one of the most informative and productive experimental system for studying carcinogenesis (Sills et al., 2001, Toxicol Letters 120:187–198), cancer therapy (Malkinson, 2001, Lung Cancer 32(3):265–279; Hoffman RM., 1999, Invest New Drugs 17(4):343–359), and cancer chemoprevention (Yun, 1999, Annals NY Acad Sci. 889:157–192). Cancer research started with transplanted tumors in animals which provided reproducible and controllable materials for investigation. Pieces of primary animal tumors, cell suspensions made from these tumors, and immortal cell lines established from these tumor cells propagate when transplanted to animals of the same species.
To transplant human cancer to an animal and to prevent its destruction by rejection, the immune system of the animal are compromised. While originally accomplished by irradiation, thymectomy, and application of steroids to eliminate acquired immunity, nude mice that are athymic congenitally have been used as recipients of a variety of human tumors (Rygaard, 1983, in 13th International Cancer Congress Part C, Biology of Cancer (2), pp37–44, Alan R. Liss, Inc., NY; Fergusson and Smith, 1987, Thorax, 42:753–758). While the athymic nude mouse model provides useful models to study a large number of human tumors in vivo, it does not develop spontaneous metastases and are not suitable for all types of tumors. Next, the severe combined immunodeficient (SCID) mice is developed in which the acquired immune system is completely disabled by a genetic mutation. Human lung cancer was first used to demonstrate the successful engraftment of a human cancer in the SCID mouse model (Reddy S., 1987, Cancer Res. 47(9):2456–2460). Subsequently, the SCID mouse model have been shown to allow disseminated metastatic growths for a number of human tumors, particularly hematologic disorders and malignant melanoma (Mueller and Reisfeld, 1991, Cancer Metastasis Rev. 10(3):193–200; Bankert et al., 2001, Trends Immunol. 22:386–393). With the recent advent of transgenic technology, the mouse genome has become the primary mammalian genetic model for the study of cancer (Resor et al., 2001, Human Molec Genet. 10:669–675).
While surgery, chemotherapeutic agents and radiation are useful in the treatment of ovarian cancer, there is a continued need to find better treatment modalities and approaches to manage the disease that are more effective and less toxic, especially when clinical oncologists are giving increased attention to the quality of life of cancer patients. The present invention provides an alternative approach to cancer therapy and management of the disease by using an oral composition comprising yeasts.
2.2 Yeast-Based Compositions
Yeasts and components thereof have been developed to be used as dietary supplement or pharmaceuticals. However, none of the prior methods uses yeast cells which have been cultured in an electromagnetic field to produce a product that has an anti-cancer effect. The following are some examples of prior uses of yeast cells and components thereof:
U.S. Pat. No. 6,197,295 discloses a selenium-enriched dried yeast product which can be used as dietary supplement. The yeast strain Saccharomyces boulardii sequela PY 31 (ATCC 74366) is cultured in the presence of selenium salts and contains 300 to about 6,000 ppm intracellular selenium. Methods for reducing tumor cell growth by administration of the selenium yeast product in combination with chemotherapeutic agents is also disclosed.
U.S. Pat. No. 6,143,731 discloses a dietary additive containing whole β-glucans derived from yeast, which when administered to animals and humans, provide a source of fiber in the diet, a fecal bulking agent, a source of short chain fatty acids, reduce cholesterol and LDL, and raises HDL levels.
U.S. Pat. No. 5,504,079 discloses a method of stimulating an immune response in a subject utilizing modified yeast glucans which have enhanced immunobiologic activity. The modified glucans are prepared from the cell wall of Saccharomyces yeasts, and can be administered in a variety of routes including, for example, the oral, intravenous, subcutaneous, topical, and intranasal route.
U.S. Pat. No. 4,348,483 discloses a process for preparing a chromium yeast product which has a high intracellular chromium content. The process comprises allowing the yeast cells to absorb chromium under a controlled acidic pH and, thereafter inducing the yeast cells to grow by adding nutrients. The yeast cells are dried and used as a dietary supplement.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of the claims of the present application. All statements as to the date or representations as to the contents of these documents are based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.